Peroxisome Proliferator-Activated Receptor Gamma in Obesity and Colorectal Cancer: the Role of Epigenetics.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor that is deregulated in obesity. PPARγ exerts diverse antineoplastic effects. Attempting to determine the clinical relevance of the epigenetic mechanisms controlling the expression PPARγ and susceptibility to colorectal cancer (CRC) in obese subjects, this study investigated the role of some microRNAs and DNA methylation on the deregulation of PPARγ. Seventy CRC patients (34 obese and 36 lean), 22 obese and 24 lean healthy controls were included. MicroRNA levels were measured in serum. PPARγ promoter methylation was evaluated in peripheral blood mononuclear cells (PBMC). PPARγ level was evaluated by measuring mRNA level in PBMC and protein level in serum. The tested microRNAs (miR-27b, 130b and 138) were significantly upregulated in obese and CRC patients. Obese and CRC patients had significantly low levels of PPARγ. A significant negative correlation was found between PPARγ levels and the studied microRNAs. There was a significant PPARγ promoter hypermethylation in CRC patients that correlated to low PPARγ levels. Our results suggest that upregulation of microRNAs 27b, 130b and 138 is associated with susceptibility to CRC in obese subjects through PPARγ downregulation. Hypermethylation of PPARγ gene promoter is associated with CRC through suppression of PPARγ regardless of BMI.

Polymorphisms of α1-antitrypsin and Interleukin-6 genes and the progression of hepatic cirrhosis in patients with a hepatitis C virus infection.

Hepatitis C virus (HCV) infection represents a serious health problem. The -174 G/C mutation in the pro inflammatory cytokine interleukin-6 (IL-6) is associated with developing liver diseases. Likewise, the S and Z mutations in the serine protease inhibitor α1-antitrypsin (A1AT) are associated with pulmonary emphysema and/or liver cirrhosis. We explored the distribution of the single nucleotide polymorphisms (SNPs) of IL-6 and A1AT genes in chronic HCV-infected patients and evaluated their impact on the progression of liver cirrhosis. One hundred and fifty Egyptian HCV-infected patients together with 100 healthy controls were enrolled in this study. The patient groups were subdivided into chronic hepatitis patients (n = 85) and cirrhotic patients (n = 65). The SNP of IL-6 (-174 G/C, rs1800795), A1AT Z mutation (342 Glu/Lys, rs28929474) and A1AT S mutation (264 Glu/Val, rs17580) were determined using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Cirrhotic patients exhibited significantly increased frequency of the A1AT S allele compared with the controls (34.6 vs. 5.0%), while the chronic hepatitis patients showed a higher frequency of the A1AT Z allele compared with the controls (14.7 vs. 2.5%). Remarkably, IL-6 (CC genotype) was detected only in the chronic hepatitis patients. Multivariate regression analysis showed that aspartate transaminase (AST) and the S alleles of A1AT, represented as SS+MS genotypes, were significantly independent predictors for development of liver cirrhosis. We concluded that inheritance of deficient S and Z alleles of the A1AT gene but not IL-6 (-174 G/C), were associated with progressive liver diseases.

Effect of simvastatin and naringenin coadministration on rat liver DNA fragmentation and cytochrome P450 activity: an in vivo and in vitro study.

This study was designed to assess the effect of naringenin (NRG) on simvastatin (SV)-induced hepatic damage in rat and to investigate the effects of these drugs on cytochrome P450 (CYP) 2E1 and 3A1/2 isoforms in order to evaluate the possibility of their coadministration. Hepatic damage in rat was induced by SV (20 and 40 mg/kg/day, po for 30 days). The protective effect of NRG (50 mg/kg/day, po) was identified by estimating liver functions and oxidative stress markers such as lipid peroxidation, reduced glutathione, superoxide dismutase, glutathion s-transferase, and catalase as well as protein profile. DNA fragmentation and histopathological study were carried out to confirm the hepatic damage. An in vitro study was conducted to further evaluate the effect of SV and/or NRG administration on the activities of two microsomal CYP isoenzymes including CYP2E1 and CYP3A1/2. SV exerted an oxidative stress which may contribute to the hepatotoxicity. Administration of NRG in combination with SV significantly improved the liver functions, state of oxidative stress, protein profile, DNA fragmentation, and the histopathological changes. SV and/or NRG have a potential to inhibit CYP3A1/2 and CYP2E1. This study concluded that concurrent administration of NRG with SV provided a protection of liver tissue against the SV-induced hepatic damage. The inhibition of CYP2E1 and CYP3A1/2 by the SV and NRG should be taken into account in order to adjust doses to avoid interaction between SV and NRG and adverse effects of SV.

Protective effect of vitamin E, beta-carotene and N-acetylcysteine from the brain oxidative stress induced in rats by lipopolysaccharide.

The major goal of this study was to examine the ability of several antioxidants namely, vitamin E, beta-carotene and N-acetylcysteine, to protect the brain from oxidative stress induced by lipopolysaccharide (LPS, endotoxin). LPS, a component of the bacterial wall of gram-negative bacteria, has been recognized as one of the most potent bacterial products in the induction of host inflammatory responses and tissue injury and was used in this study to mimic infections. LPS injection resulted in a significant increase in the stress indices, plasma corticosterone and glucose concentration, a significant alteration of the brain oxidative status observed as elevation of the level of malondialdehyde (MDA, index of lipid peroxidation) and reduction of reduced glutathione (GSH), and a disturbance in the brain energy metabolism presented as a reduction in the ATP/ADP ratio and an increase in the mitochondrial/cytosolic hexokinase ratio. However, the activities of brain superoxide dismutase and Na+, K+-ATPase and contents of cholesterol and phospholipids were not altered. Administration of the aforementioned antioxidants prior to LPS injection ameliorated the oxidative stress by reducing levels of MDA, restoring GSH content and normalizing the mitochondrial/cytosolic hexokinase ratio in the brain in addition to lowering levels of plasma corticosterone and glucose. In conclusion, this study showed the increased free radical generation during infections and LPS-induced stress. It also suggests that brain oxidative status and energy is disturbed.

Nicotine and stress: effect on sex hormones and lipid profile in female rats.

This work aimed to study the changes in sex hormones and lipid profile in adult female albino rats subjected to treatment with nicotine (N), immobilization stress (S), or their combinations (N+S). These treatments were applied either for one day (T1) or daily for 10 days (T10), after which rats in the estrus stage were used for the determination of plasma corticosterone (CS), serum sex hormones as progesterone (P), estrogen (E), FSH, LH and serum lipid profile including total cholesterol (TC), HDL-C, LDL-C, triacylglycerol (TG) and non esterified fatty acids (NEFA). It was clear that either N or S raised plasma CS and serum P levels in both the treatment regimens and that N+S induced a higher level of these hormones compared to each treatment alone. Serum E level was only elevated during T10 regimen only. An increase in serum LH level was only observed after a single exposure to either N or S, however their combination abolished the stimulatory effect induced by each treatment alone. Serum FSH was not altered by exposure to either N or S alone in both regimens, but in the T10 regimen their combination significantly lowered FSH level. Regarding the effect on serum lipid profile, serum TC was increased in all T10 regimen groups. LDL-C was increased by N+S treatment in both regimens, however no change in HDL-C level was observed in all groups. Serum NEFA was increased in all the treated groups during T10 regimen, while in the T1 regimen NEFA level was only elevated by the combination N+S. Serum TG was insignificantly altered in all the treated groups. The observed changes in the lipid pattern were attributed to the alterations occurred in CS and female sex hormones that caused by N, S or their combinations.

The priming effects of some human interleukins on the production of leukotrienes by calcium ionophore stimulated leukocytes.

This study demonstrates the changing levels of leukotrieneB4 (LTB4) and leukotrieneC4 (LTC4) generated by human white blood cells primed with different human interleukins IL-3, IL-5, IL-6, IL-8 and with human hematopoietic growth factor granulocyte-macrophage colony stimulating factor (GM-CSF). Preincubation of white blood cells at 37 degrees C for 30 min with different human interleukins significantly increased leukotriene production in white blood cells preincubated with diluent control while IL-3 was without priming effects. Addition of exogenous arachidonic acid to non primed white blood cells increased the production of leukotrienes in response to the calcium ionophore (A23187). The enhancement of the leukotrienes production by white blood cells stimulated by A23187 was only observed when the cells stimulated for periods of 2 min or less. The results reveal that GM-CSF, IL-4, IL-6 and IL-8 belong to particular set of cytokines with potent modulating effect on inducing inflammatory mediators released by white blood cells, while IL-3 was ineffctive.

Hypoglycemic and antihyperglycemic effects of Zizyphus spina-christi in rats.

Zizyphus is one of the plants commonly used in Egyptian folk medicine for the treatment of different diseases. The present study aims to investigate the effect of the butanol extract of Zizyphus spina-christi leaves as well as christinin-A, its principle saponin glycoside, in normal and streptozotocin-diabetic rats. In normal rats, treatment in both cases for one and four weeks produced insignificant changes in all studied parameters. However, in diabetic rats, both treatments significantly reduced serum glucose level, liver phosphorylase and glucose-6-phosphatase (G-6-pase) activities, and significantly increased serum pyruvate level and liver glycogen content after 4 weeks treatment. There was also marked improvement in glucose utilization in diabetic rats in both cases. Serum insulin and pancreatic cAMP levels showed significant increases in diabetic rats treated for a period of 4 weeks with the butanol extract.

Clinical value of thymidine kinase and tissue polypeptide specific antigen in breast cancer.

Thymidine kinase (TK) and tissue polypeptide specific antigen (TPS) were determined in breast cancer (BC) patients (n = 83), normal healthy women (n = 30) and 18 women with different benign mastopathies. Mean serum levels of TK and TPS in BC patients showed significant increases from their corresponding levels in healthy women and those with benign breast diseases. Diagnostic sensitivity of TK and TPS was 47% and 58% respectively at the selected cut-off values 8 U/L for TK and 110 U/L for TPS (96% specificity). Pre-operative serum levels of TK and TPS showed significant correlation with the stage of disease and with other classical prognostic factors; clinical stage, tumour size, lymph node involvement and distant metastasis. Nineteen BC patients were followed-up by serial monthly measurements of TK and TPS (4-10 samples). Both markers seemed to be valuable in monitoring drug efficacy. TK and TPS were able to detect systemic recurrence before clinical diagnosis (average 2 months lead time). TPS was greatly affected by liver diseases.

Effect of vitamin C administration in modulating some biochemical changes in arthritic rats.

Two phases of arthritis, acute phase (four days after adjuvant inoculation) and chronic phase (21 or 29 days after adjuvant inoculation) were studied in male rats. The effect of administration of vitamin C in a daily oral dose of 50 mg/kg body wt for four and 21 days starting on the day of adjuvant inoculation and for 7 days starting 21 days after adjuvant inoculation against these phases of arthritis was demonstrated. Results showed that prolonged administration of vitamin C (21 days) increased the lowered serum sulphydryl (SH-groups) to prearthritic values while it decreased the elevated level of blood glutathione (GSH) of arthritic rats. However, neither (four-day) nor seven-day treatment with vitamin C exerted any significant changes in these parameters. The results showed also a slight significant increase in the level of erythrocyte superoxide dismutase activity (SOD) [1.15.1.1] upon seven-day treatment with vitamin C. Meanwhile, four-, 21- or seven-day treatment with vitamin C produced no significant change in the elevated levels of serum ceruloplasmin (Cp) and alpha 2-macroglobulin (alpha 2-M) of arthritic rats. However, 21-day and 7-day administration of vitamin C has improved the lowered A/G ratio in these animals. The improvement in these parameters after prolonged administration of vitamin C was explained in the light of the antioxidant property of this vitamin and suggests a beneficial role for it in the treatment of arthritis.

Biochemical changes in arthritic rats under the influence of vitamin E.

Two phases of adjuvant arthritis, acute phase (4 days after adjuvant inoculation) and chronic phase (21 and 29 days after adjuvant inoculation) were studied in male rats. The effect of administration of vitamin E in a daily oral dose of 147 mg/kg body wt. for one week against these phases of arthritis were demonstrated before and after adjuvant inoculation. Results showed that administration of the vitamin before and after adjuvant inoculation increased the lowered serum-SH group in arthritic rats so that their level was restored to pre-arthritic values especially in chronic treated group. Meanwhile, these treatments produced no change in the increased level of blood GSH or erythrocyte SOD activity of arthritic rats. The results showed also that administration of vitamin E before adjuvant inoculation increased significantly the level of alpha 2-M while it did not alter the increased serum Cp in acute phase. However, administration of the vitamin after adjuvant inoculation failed to exert any change in these parameters. In the meantime, these treatments tended to increase the lowered A/G of arthritic rats in different phases especially in acute one. These observations suggest that antioxidants such as vitamin E may be beneficial for arthritis.